Longitudinal Analysis of the Costs Associated with Inpatient Initiation and Subsequent Outpatient Continuation of Proton Pump Inhibitor Therapy for Stress Ulcer Prophylaxis in a Large Managed Care Organization

BACKGROUND: Proton pump inhibitor (PPI) therapy is commonly initiated in hospitals for a variety of reasons including stress ulcer prophylaxis. Outpatient use of inpatient-initiated PPI use may be medically unwarranted. OBJECTIVES: To (a) describe in a longitudinal analysis the incidence and reasons for hospital initiation of PPI therapy, (b) identify the proportion of members continued on PPI therapy at hospital discharge that is not medically warranted, and (c) estimate the total costs incurred by the managed care organization (MCO) and its members due to inappropriate continuation of hospital-initiated PPI therapy after discharge. METHODS: A retrospective review of de-identified medical and pharmacy claims was performed to identify commercial and Medicare patients with an acute care hospital admission and subsequent discharge on a PPI from January 1, 2003, through December 31, 2006, in an MCO with approximately 2.5 million members with medical and prescription drug coverage. Hospital-initiated PPI therapy was assumed based on the presence of a paid pharmacy claim for a PPI within the 30-day period following hospital discharge. All patients who during the study period had (a) no PPI claims during the 90 days prior to an inpatient admission, followed by (b) a hospital stay, and (c) at least 1 pharmacy claim for a PPI during 30 post-discharge days were included in this analysis. Patients with PPI claims during the 90 days prior to their inpatient admission were excluded from analysis as this use was assumed to be appropriate. Any member (a) initiated on PPI therapy during hospital admission without a medically appropriate diagnosis, either primary or secondary, 3 months prior to or during hospitalization and (b) continuing therapy after discharge, as determined by at least 1 pharmacy claim for a PPI during the first 30 post-discharge days, was categorized as an inappropriate user. For the sample subgroup with inappropriate PPI use, costs due to inappropriate PPI therapy were calculated as the total cost incurred by the MCO and its members including ingredient cost, dispensing fees, member copayments, and coinsurance for PPI claims during the first 30 days after hospital discharge. RESULTS: Of 29,348 study-eligible members, 68.8% (n = 20,197) were prescribed a PPI inappropriately at hospital discharge. Rates of inappropriate PPI use were approximately equal for patients who stayed in the intensive care unit or coronary care unit (ICU/CCU) versus non-ICU/CCU patients (68.7% vs. 68.9%, respectively, P = 0.796 using the Pearson chi-square test). Over the 4-year period of this analysis, the total cost to the MCO and its members associated with inappropriate continuation of PPI therapy during the first 30 days after hospital discharge was $3,013,069. CONCLUSIONS: Increased health care costs associated with the utilization of PPIs can result from the inappropriate prescribing and continuation of PPI therapy after hospital discharge. Education of health care practitioners regarding medication reconciliation in general, and regarding continuation of PPI therapy specifically, is needed to increase responsible postdischarge medication utilization.

• According to the Drug Trend Report by the pharmacy benefits management company Express Scripts, U.S. commercial insurers spent approximately $63 per member per year for gastrointestinal medications, primarily proton pump inhibitors (PPIs), in 2007. • Although PPI therapy is often initiated in hospitalized patients for stress ulcer prophylaxis (SUP), the use of PPIs for this specific indication is questionable because of lack of institutional guidelines regarding this subject. • An estimated 10%-27% of patients discharged on acid-suppressive therapy meet the requirements for appropriate use of PPI therapy, indicating that a large proportion of patients are on therapy that is not otherwise indicated.

R E S E A R C H
• This study identifies a possible source of overprescribing of PPIs, hospital-initiated therapy that is unnecessarily continued after discharge. • In a sample of commercially insured and Medicare patients discharged on a hospital-initiated PPI from January 1, 2003, through December 31, 2006, 68.8% lacked an appropriate medical indication for PPI use, contributing to total PPI drug cost of $3,013,069 during the first 30 post-discharge days. • The rates of inappropriate PPI use for intensive care unit/coronary care unit (ICU/CCU) patients and non-ICU/CCU patients were comparable (68.7% vs. 68.9%, respectively, P = 0.796 using the Pearson chi-square test), indicating that the appropriate utilization of PPI therapy within the institutional setting has not yet been achieved in accordance with the multiple risk factors warranting SUP. • Given the large amount of dollars spent in this drug therapy category, an intervention such as medication reconciliation at the point of discharge is necessary in the hospital setting.

What this study adds
Note: This article is the subject of an editorial that appears on pages 134-140 of this issue. S tress-related mucosal damage is an erosive process of the gastroduodenum that occurs among most patients admitted to the intensive care unit (ICU). 1,2 Evidence of stressrelated mucosal damage occurs within 24 hours of admission to an ICU. This damage can progress rapidly to erosive ulceration, often leading to major complications such as gastrointestinal (GI) bleeding. 3 Therefore, stress ulcer prophylaxis (SUP) has traditionally been used in this patient population to minimize morbidity and mortality associated with clinically significant GI bleeding. [4][5][6] Studies, however, demonstrate a significant decrease in the incidence of clinically important bleeding from stress ulceration in the absence of specific pharmacotherapy due to advances in the management of critically ill patients. 7 Based on these findings, universal prophylaxis may not be indicated, especially in patients lacking an indication for acid-suppressive therapy. Despite the evidence, current practice guidelines suggest that prophylaxis with acid-suppressive therapy should be routinely initiated for patients at risk for stress ulceration. 2 Of the numerous independent risk factors for stress ulceration, evidence suggests that coagulopathy and/or respiratory failure requiring mechanical ventilation for more than 48 hours are associated with the highest risk of GI bleeding. 6 Despite these reports, several studies demonstrate that even general internal medicine patients lacking an indication for acid-suppressive therapy are commonly started on therapy for the purpose of preventing stress ulceration. 8,9 More importantly, it appears that acid-suppressive medications are inappropriately continued after hospital discharge, resulting in further unnecessary expenditure of resources and increases in economic cost. 5,9 Also, chronic use of proton pump inhibitors (PPIs) is associated with adverse events that can be especially severe among elderly patients. 10,11 Although acid-suppressive therapy, including PPIs, may be used to manage many conditions in an inpatient setting, it appears to play a significant role in the treatment of stressrelated mucosal damage. Conventional therapies used to manage this state include antacids, histamine-2 receptor blocker (H2-blockers), or sucralfate. 1,2 Evidence suggests that all 3 drug classes are efficacious in reducing the occurrence of clinically significant GI bleeding due to stress-related mucosal damage. [12][13][14][15] Although H2-blockers have consistently been used as primary therapy for SUP, PPIs have evolved into a first-line therapy in an increasing percentage of critical care patients despite limited information about their use in this population. 16 Factors contributing to the increased utilization of this class of drugs include the prolonged duration of action combined with fewer adverse events versus conventional therapies. 4 This report provides an analysis of the degree to which inappropriate continuation of PPI therapy occurs at hospital discharge based on a longitudinal retrospective analysis of an administrative claims database for dates of service between January 1, 2003, and December 31, 2006. Data were obtained from outpatient pharmacy claims and medical claims from a large managed care Although SUP is potentially appropriate only for patients admitted to the ICU or coronary care unit (CCU), it is possible that PPIs are widely prescribed for those patients also admitted to a general internal medicine ward, either inappropriately or for appropriate indications unrelated to SUP. The objectives of this longitudinal analysis were to (a) examine the extent to which inappropriate continuation of PPI therapy occurs upon hospital discharge, (b) estimate the costs associated with inappropriate prescribing of PPIs, and (c) describe the incidence and reasons for hospital initiation of PPI therapy.

■■ Methods
Medical and pharmacy claims were the primary data source for this analysis. Patients were initially selected if they had at least 1 claim for a PPI (rabeprazole, esomeprazole, lansoprazole, omeprazole, or pantoprazole), identified by specific national drug code (NDC) numbers, with a date of service within 90 days prior to an admission date or 30 days following a discharge date for an acute care hospitalization from January 1, 2003, through December 31, 2006. Continuous eligibility for medical and pharmacy benefits throughout the 4-year study period was required for inclusion in the sample. To ensure that PPI claims prior to hospitalization were captured for those patients with any type of hospital admission early in 2003, pharmacy claims data were extracted for dates of service beginning October 1, 2002. For patients with more than 1 admission during the study time frame who met the study criteria, each admission was counted separately.
Inpatient admissions were primarily identified by inpatient "place of service" and revenue codes indicating accommodation (room and board). Claims are categorized and stored in this health plan database as inpatient, outpatient facility, major medical, or professional, depending on the type of service provided and the billing form used. Outpatient provider care is generally billed through the 1500 Health Insurance Claim Form using Current Procedural Terminology (CPT) or Healthcare Common Procedure Coding System (HCPCS) codes. The Uniform Bill (UB)-04, also known as the Centers for Medicare & Medicaid Services (CMS)-1450 Claim Form, is a facility billing form that identifies in the "place of service" field whether the service was provided in a hospital, home care, clinic, or other facility and further defines whether the service was provided in the inpatient or outpatient setting. Additional fields further define the type of service provided using revenue codes. Revenue codes 020x and 021x were used to identify ICU and CCU admissions, respectively. Therefore, claims specific for inpatient services were used exclusively to identify hospitalizations.
The following data extraction logic was used to target members who were started on a PPI during a hospital admission and days prior to or during the hospitalization was classified as inappropriately using a PPI. A list of appropriate diagnoses for the initiation of acid-suppressive therapy is reported in Table  1. The diagnoses listed in Table 1 represent any condition that would increase a patient's chance of experiencing a GI bleed. These diagnoses were identified by the health plan's clinical pharmacy and informatics team, which includes pharmacists with residency training, nurses, and other health care professionals. Assessments were based on clinical experience rather than U.S. Food and Drug Administration (FDA) approved indications because drug label information does not always reliably indicate clinically appropriate use.
For members without an appropriate diagnosis for prescribing, a period of 30 days post-discharge was used as a conservative time frame to calculate the estimated total costs of inappropriate prescribing of PPI therapy. Costs due to inappropriate PPI therapy were calculated as the total pharmacy cost incurred by the MCO and its members, including dispensing fees, ingredient cost, member copayments, and coinsurance.

■■ Results
A total of 45,498 continuously enrolled patients were hospitalized during the course of the study period and were dispensed at least 1 outpatient prescription for a PPI during the first 30 post-discharge days ( Figure 1). Of these, 16,150 patients were eliminated from this analysis because they had at least 1 pharmacy claim for a PPI within 90 days prior to admission (assumed to be appropriately prescribed), leaving 29,348. Of these, 10,837 (36.9%) spent time in an ICU or CCU during their hospital stay. The number (percentage) of patients having an appropriate diagnosis for the initiation of acid suppression therapy, either within the 90 days prior to the hospital stay or at any time during the hospital stay, was 9,151 (31.2%). The remaining 20,197 (68.8%) patients were then categorized as inappropriately receiving a prescription for a PPI.
Approximately 37.0% of members (3,389/9,151) who were appropriately prescribed a PPI spent some time in the ICU or CCU, with 23.9% (2,188/9,151) of members spending time in the ICU and 13.1% (1,201/9,151) of members in the CCU. Table  2 provides additional data regarding the incidence rates and costs associated with inappropriate PPI use in the 30 days subsequent to hospital discharge. More importantly, the rates of inappropriate use of a PPI for ICU/CCU patients versus non-ICU/CCU patients were virtually identical (68.7% vs 68.9%, respectively, P = 0.796 using the Pearson chi-square test). Inappropriate continuation of PPIs decreased slightly over the 4 years of the study; however, the total cost associated with inappropriate continuation of PPI therapy remained high at a total of $3,013,069 over the 4-year study period including costs paid by both the MCO and the member. Table 3 identifies the top 20 diagnosis categories based on ICD-9-CM codes that were present when PPI therapy was whose PPI therapy was inappropriately continued after discharge. The study sample included all continuously eligible patients during the study period who had (a) no PPI claims during the 90 days prior to an inpatient admission, followed by (b) a hospital stay, and (c) a least 1 pharmacy claim for a PPI during the first 30 post-discharge days. The rationale for criterion (a), which eliminated members who were prescribed a PPI prior to hospitalization, was to avoid exaggeration of inappropriate prescribing at discharge, since the member may have had an appropriate indication prior to admission that may not have been accounted for upon discharge from the hospital.
Any patient in the sample who lacked an appropriate International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis (primary or secondary) 90  initiated and continued inappropriately, that is, without an appropriate medical indication. Among patients with inappropriate continuation of PPI therapy, the most common diagnosis was ischemic heart disease (16.1%).

■■ Discussion
According to the 2007 Drug Trend Report compiled by the pharmacy benefits management company Express Scripts, U.S. commercial insurers spent approximately $63 per member per year for GI medications, primarily PPIs. 17 Although some clinicians may challenge the clinical equivalence and therapeutic substitution of PPIs, 18-21 all drugs within this therapeutic category are known to be effective in both healing ulcerations and alleviating the symptoms of reflux. 22,23 The American Society of Health-System Pharmacists (ASHP) promulgated national guidelines for SUP in 1999. 2 An update to these guidelines was released in 2004 by Allen et al. 24 More importantly, these guidelines focus on the use of H2-blockers and sucralfate as first-line agents for SUP; however, it is known that PPIs are the most frequently used acidsuppressive medications for SUP. Moreover, published guidelines do not recommend the use of SUP for adult patients in non-ICU settings. 2,24 Therefore, before PPIs can be considered as a first-line therapy for SUP either in the ICU or non-ICU settings, larger comparative studies and pharmacoeconomic analyses are needed. 4 Several studies published since the release of ASHP guidelines in 1999 have reported significant overuse of SUP among patients in non-ICU settings. Nardino et al. (2000) reviewed the use of acid-suppressive therapy (H2-blockers, PPIs, or sucralfate) in 226 patients admitted to a general adult medicine service in a community hospital and found that 54% of patients received acidsuppressive therapy, yet 65% of prescriptions were not indicated. Of patients discharged on acid-suppressive therapy, unnecessary use was identified in 67%. 25 Another retrospective chart review of 213 patients admitted to the University of Michigan Hospital non-CCU general medicine service conducted by Pham et al. (2006) provided similar results. 26 Twenty-nine percent of patients were taking an acid suppressant prior to admission, 33% of whom were taking a PPI. Once admitted, 71% of patients used acid suppressants, 84% of whom used a PPI, and 54% of patients were prescribed acid suppressants at discharge. Depending on acceptable criteria for long-term use of acid-suppressive therapy, anywhere from 10%-27% of those patients discharged on acidsuppressive therapy met the requirements for appropriate use. In essence, both studies indicate excess usage of acid suppressants in both the inpatient and outpatient settings.
Inappropriate use of SUP has been associated with increased costs specific to both inpatient and outpatient use. Heidelbaugh and Inadomi (2006) conducted a retrospective chart review of  admissions to family medicine and general internal medicine teaching services. 8 Of 1,769 patients screened, 391 (22.1%) received acid-suppressive therapy for SUP without an indication as determined by the ASHP guidelines. Fifty-four percent of these patients were sent home with a prescription for antisecretory medication. An economic analysis of these data found that the inpatient cost associated with inappropriate SUP was more than $11,000 over a 4-month period. Assuming full medication compliance, the estimated annualized outpatient cost was more than $67,000. 8 The small but significant association between the chronic use of PPI therapy and specific safety concerns has generated controversy. Adverse effects are typically mild but may be more serious with the chronic use of acid-suppressive therapy or in patients with renal impairment. 2 Also, due to the common path of metabolism of numerous drugs through the cytochrome P450 system and the disruption caused by PPI therapy to specific drugs requiring an acidic environment for absorption, PPIs have the potential to   interact with many drugs. [27][28][29] Furthermore, the long-term effects associated with the reduction of the acid content within the GI tract may increase the risk of infection by pathogens normally eradicated by the low pH. Multiple studies have evaluated the use of gastric acid-suppressive agents and the risk of communityacquired pneumonia (CAP) and Clostridium difficile-associated disease (CDAD). 10,11,30,31 A retrospective analysis conducted by Laheij et al. (2004) examined the association between the use of gastric acid-suppressive drugs and the incidence of CAP. 30 The authors concluded that users of acid-suppressive agents (PPIs and H2-blockers) had a frequency rate of pneumonia nearly twice that of non-users. Dial et al. (2005) conducted a similar analysis to assess the potential risk for CDAD. 31 Findings of this analysis indicated that exposure to acid-suppressive therapy (especially PPIs) increased the risk of community-acquired CDAD (adjusted rate ratio for PPIs = 2.9, 95% confidence interval [CI] = 2.4-3.4). Therefore, while a general consensus is still lacking regarding the association between PPIs and the onset of CDAD and CAP, the potential for increased morbidity exists with the use of these agents. 10,11 In our analysis, the rate of inappropriate prescribing of PPIs was high at 68.8%. Although rates of inappropriate prescribing upon discharge remained fairly constant from 2003 through 2006, a slight decrease was observed from 70.4% in calendar year 2004 to 67.2% in calendar year 2006. Additionally, we expected that the majority of PPI utilization within the inpatient setting would be for SUP; however, the majority (63.1%) of patients (18,511/29,348) in the analysis was never in the ICU or CCU. To further support this finding, the rates of inappropriate PPI use were comparable for patients admitted to a general medicine ward and patients admitted to the ICU/CCU. Finally, of the 20,197 patients inappropriately prescribed a PPI, only 7,448 (36.9%) spent time in the ICU or CCU units. These findings indicate that appropriate utilization of PPI therapy within the institutional setting has not yet been achieved according to the multiple risk factors warranting SUP.

Educational Intervention
Increased utilization of PPIs is compounded by the unnecessary continuation of acid-suppressive therapy subsequent to hospital discharge. Because our data show that the majority of PPI therapy was initiated outside the ICU setting, provider education regarding the implementation of SUP guidelines is essential. Such interventions may help to minimize health care costs associated with SUP without compromising patient outcomes. For example, a study performed at the Carolinas Medical Center found an estimated annual savings of $102,895 in patient charges and $11,333 in actual drug costs in a trauma ICU attributable to the implementation of SUP guidelines. 32 Another ICU-based study performed in a teaching hospital in Vancouver, British Columbia, concluded that after the introduction of a guideline for SUP administration, the rate of appropriate therapy increased from 75.8% to 91.1%, and medication costs decreased from CAN$2.50 per day to CAN$1.30 per day without any statistically significant difference in clinical outcomes. 33 Pharmacists practicing within the institutional setting will play a key role in assessing the appropriateness of continuation of SUP therapy or any other diagnosis for which a PPI is prescribed, through the implementation of interventions such as stop orders specific to PPIs. Furthermore, our results indicate that there is a need for complete and accurate medication reconciliation at the point of hospital discharge. If the unnecessary continuation were caught at that point, the savings to the health care system, as well as reduction in morbidity associated with prolonged PPI use, could be substantial.
From a managed care perspective, the implementation of utilization management tools, such as step therapy and dose/ duration limits, has helped to limit the increase in cost associated with this class of drugs. 34,35 However, the results of this analysis indicate that additional interventions are required. Provider education by means of academic detailing, combined with routine drug utilization reviews specific to this area of clinical practice, may help to further control drug costs associated with the inappropriate continuation of PPIs upon discharge from a hospital. Additionally, pay-for-performance measures for hospitals and/ or physicians may be another tool to help encourage appropriate utilization and follow-up.

Limitations
All of the customary limitations of a retrospective claims study apply to this analysis. First, because there is no ICD-9-CM code specific to SUP, it was assumed that patients lacking an appropriate indication for acid-suppressive therapy received a PPI for SUP. Second, incomplete or miscoded diagnoses could have resulted in errors in capturing a diagnosis associated with appropriate use of a PPI, potentially affecting the inappropriate prescribing rates determined in this analysis. Third, we may have overestimated the actual use of PPIs attributed to SUP during hospitalization and used inappropriately after discharge because of assumptions that were necessary in this study. For example, the 90-day look-back period may have failed to identify actual prior PPI use, and the inclusion criterion for apparent new use of a PPI up to 30 days after the hospital discharge may have falsely identified new PPI use that was unrelated to SUP or the hospital admission. However, this possible overestimation of inappropriate use would be mitigated somewhat by post-discharge use of over-the-counter (OTC) Prilosec, which would not have been captured in the pharmacy claims data.
Fourth, another cited reason for acid-suppressive therapy in the literature is high-dose corticosteroid therapy in the presence of other risk factors warranting SUP because of the risk of a GI bleed. 2 Diagnoses such as bronchitis, asthma, colitis, arthropathy, and renal conditions such as nephritis, nephritic syndrome, and nephrosis are commonly treated with corticosteroid therapy.

Longitudinal Analysis of the Costs Associated with Inpatient Initiation and Subsequent Outpatient Continuation of Proton Pump Inhibitor Therapy for Stress Ulcer Prophylaxis in a Large Managed Care Organization
In our analysis, these conditions were among the top 20 diagnostic groupings for which inappropriate prescribing occurred. Although prescribing may be indicated in select instances, corticosteroid therapy alone is not an independent risk factor warranting SUP. 2 Fifth, we did not assess the extent of immediate post-discharge use of PPIs that might be defined as appropriate concomitant use with nonsteroidal anti-inflammatory drugs and warfarin, such as in patients following orthopedic surgery or in cardiac patients.

■■ Conclusion
Some of the increased health care costs associated with the utilization of PPIs originate from inappropriate prescribing during hospitalization and continuation of PPI therapy after hospital discharge. Our study confirmed that PPI therapy was initiated in an ICU or CCU setting only 36.9% of the time, presumably for SUP. Also, approximately 70% of patients initiated on PPI therapy were discharged with a prescription for PPI therapy in the absence of a medical need to continue such therapy. Over the 4-year period of this analysis, the total cost associated with inappropriate continuation of PPI therapy in the first 30 days following hospital discharge was approximately $3 million. Further education of health care practitioners regarding the appropriate use of PPI therapy based on clinical indication is needed.